Ischemia is a condition characterized by an interruption or inadequate supply of blood to tissue, which causes oxygen deprivation in the affected tissue. Myocardial ischemia is a condition caused by a blockage or constriction of one more of the coronary arteries, such as can occur with atherosclerotic plaque occlusion or rupture. The blockade or constriction causes oxygen deprivation of the non-perfused tissue, which can cause tissue damage. Further, upon reperfusion with subsequent reoxygenation of the tissue, when the blood is able to flow again or the oxygen demand of the tissue subsides, additional injury can be caused by oxidative stress.
Ischemia/reperfusion injury refers to tissue damage caused by oxygen deprivation followed by reoxygenation. The effects of ischemia/reperfusion injury in a subject experiencing the condition can be fatal, particularly when the injury occurs in a critical organ such as the heart or brain.
Accordingly, compounds and compositions effective in preventing or protecting against ischemia/reperfusion would be useful pharmaceuticals. Compounds such as nitroglycerin have been used for a long period of time to help control vascular tone and protect against myocardial ischemia/reperfusion injury. However, the cause of nitroglycerin's therapeutic effect was not known until late in the last century when it was discovered that the nitric oxide molecule (NO−) was responsible for nitroglycerin's beneficial effects. In fact, the Nobel Prize was awarded in 1998 to three researchers who discovered NO−'s beneficial effects.
This discovery prompted interest in medical uses for NO−and investigations into related species such as nitroxyl (HNO/NO−), the one-electron reduction product of NO−. Angeli's salt (sodium trioxodinitrate or Na2N2O3) is a compound that decomposes to donate nitroxyl. Fitzhugh & Keefer, “Forum: Therapeutic Applications of Reactive Oxygen and Nitrogen Species in Human Disease,” Free Radical Biology & Medicine, 28(10): 1463-1469 (2000). U.S. Pat. No. 5,212,204 describes the vasodilating properties of NO− and discloses a pharmaceutical composition consisting essentially of Angeli's salt and a pharmaceutically acceptable sterile carrier, which the patent states can be useful to treat cardiac diseases that would respond favorably to a decrease in blood pressure, such as hypertension.
However, experiments testing the ability of Angeli's salt to prevent or protect against ischemia/reperfusion injury demonstrated that NO− increases ischemia/reperfusion injury. For example, Ma et al., “Opposite Effects of Nitric Oxide and Nitroxyl on Postischemic Myocardial Injury,” Proc. Nat'l Acad. Sci., 96(25):14617-14622 (1999) reported that administration of Angeli's salt to anesthetized rabbits during ischemia and 5 minutes prior to reperfusion increased myocardial ischemia/reperfusion injury. Also, Takahira et al., “Dexamethasone Attenuates Neutrophil Infiltration in the Rat Kidney in Ischemia/Reperfusion Injury: The Possible Role of Nitroxyl,” Free Radical Biology & Medicine, 31(6):809-815 (2001) reported that administration of Angeli's Salt during ischemia and 5 minutes before reperfusion of rat renal tissue contributed to neutrophil infiltration into the tissue, which is believed to mediate ischemia/reperfusion injury.
Thus, no effective therapy using nitroxyl to prevent or protect against ischemia/reperfusion injury has been developed.